Sharpless reaction Subject

The construction of key intermediate 18 can be conducted along similar lines. Sharpless asymmetric epoxidation of allylic alcohol 22 using (+)-DET furnishes epoxy alcohol 52b (Scheme 11). Subjection of the latter substance to the same six-step reaction sequence as that leading to 54a provides allylic alcohol 54b and sets the stage for a second SAE reaction. With (+)-DET as the... 

The reaction mechanisms of these transition metal mediated oxidations have been the subject of several computational studies, especially in the case of osmium tetraoxide [7-10], where the controversy about the mechanism of the oxidation reaction with olefins could not be solved experimentally [11-20]. Based on the early proposal of Sharpless [12], that metallaoxetanes should be involved in alkene oxidation reactions of metal-oxo compounds like Cr02Cl2, 0s04 and Mn04" the question arose whether the reaction proceeds via a concerted [3+2] route as originally proposed by Criegee [11] or via a stepwise [2+2] process with a metallaoxetane intermediate [12] (Figure 2). 

One of the success stories of transition metal catalysis is the rhodium-complex-catalyzed hydrogenation reaction. Asymmetric hydrogenation with a rhodium catalyst has been commercialized for the production of L-Dopa, and in 2001 the inventor, Knowles, together with Noyori and Sharpless, was awarded the Nobel Prize in chemistry. After the initial invention, (enantioselective) hydrogenation has been subject to intensive investigations (27). In general, hydrogenation reactions proceed... 

The resolution of the hot debate on the mechanism of metal-oxo mediated oxidations is one of the success stories of DFT calculations. An early publication by Sharpless on chromylchloride oxidations of alkenes10 started a long ongoing discussion11-25 on the mechanism of metal-oxo mediated oxidations. Sharpless proposed an interaction between the chromium metal and the alkene and generalized his proposal to include all metal-oxo compounds, especially osmium tetroxide and permanganate. Especially the mechanism of the reaction of osmium tetroxide with alkenes was the subject of an intense debate within the community of experimental organic chemists (Scheme 2). 

Asymmetric oxidations have followed the usual development pathway in which face selectivity was observed through the use of chiral auxiliaries and templates. The breakthrough came with the Sharpless asymmetric epoxidation method, which, although stoichiometric, allowed for a wide range of substrates and the stereochemistry of the product to be controlled in a predictable manner [1]. The need for a catalytic reaction was very apparent, but this was developed and now the Sharpless epoxidation is a viable process al scale, although subject to the usual economic problems of a cost-effective route to the substrate (see later) [2]. The Sharpless epoxidation has now been joined by other methods and a wide range of products are now available. The pow er of these oxidations is augmented by the synthetic utility of the resultant epoxides or diols that can be used for further transformations, especially those that use a substitution reaction (see Chapter 7) [1]. 

There are many asymmetric epoxidation reactions but none is as reliable or has been as widely used as the Sharpless Asymmetric Epoxidation1 (AE), the subject of this section, and the Jacobsen epoxidation, the subject of a later section in this chapter.2... 

Katsuki-Sharpless asymmetric epoxidation. Since its introduction in 1980 [10], the Katsuki-Sharpless asymmetric epoxidation (AE) reaction of allylic alcohols has been one of the most popular methods in asymmetric synthesis ([11-14]). In this work, the metal-catalyzed epoxidation of allylic alcohols described in the previous section was rendered asymmetric by switching from vanadium catalysts to titanium ones and by the addition of various tartrate esters as chiral ligands. Although subject to some technical improvements (most notably the addition of molecular sieves, which allowed the use of catalytic amounts of the titanium-tartrate complex), this recipe has persisted to this writing. 

S.2.2.4. Triazoles from Azides. Cycloadditions of this type constitute a valuable synthetic route to the triazole ring system. This is shown in Scheme 5.30. This combination dates back to the early work of Huis-gen, but in more recent times it was discovered to be subject to catalysis by Cu(I) compounds. The reactions are fast under mild conditions, have high regiospecificity, and occur in a variety of solvents including water. In addition, reaction products are easily isolated. Reactions with these characteristics have become known as comprising click chemistry this term was coined by K. B. Sharpless. The first and most commonly used reaction referred to by this name is indeed the azide-alkyne cycloaddition, and new interest has developed in triazole hemistry since the discoveiy of the copper catalysis. In addition to its use in organic... 

Enantioselectivity in this process arises from reaction of the alkene and osmium tetroxide within an asymmetric environment created by the ligand. However, the precise shape of this binding pocket and the nature of the interactions between the substrate and ligand has been the subject of some debate. Corey has advanced a model based on a U-shaped ligand conformation initially derived from an inspection of molecular models while Sharpless has proposed an L-shaped active site based on the results of molecular mechanics studies. 

Next, monoiodination of one of the two equivalent aromatic positions was required. The sample of diol 46 from the Sharpless asymmetric dihydroxylation and the sample of isomeric 46/47 produced by nonselective cis-dihydroxylation were both subjected to halogenation. The use of iodine and silver trifluoroace-tate" provided desired iodide 45 in 72% yield with minor quantities of starting material and the diiodide species isolable from the reaction mixture. 

Asymmetric Dihydroxylation Reactions. A substantial amount of work has been reported on the development of the asymmetric dihydroxylation (AD) reaction as originally described by Sharpless. A greater understanding has emerged of the functional group tolerance of the AD reaction and also its applicability towards differing alkene substitution patterns. The mechanism of the AD reaction has been the subject of intense debate especially with respect to the question of whether a [2 + 2] or [3 + 2] pathway is followed, and some insightful mechanistic studies have followed from this discussion. ... 

The mixture of isomeric acetates is converted to the corresponding mixture of alcohols and that mixture subjected to Sharpless asymmetric epoxidation. From this reaction, the chiral nonracemic epoxide 87 is isolated in 60% yield (>94% ee). Compound 87 is converted by standard transformations to 88 and 89, ultimately affording the leukotriene methyl ester LTAt-Me (90) (Scheme 27). A number of other leukotrienes (e.g., LTC4, LTD4,... 

More practical, catalytic asymmetric synthesis of key chiral DE-ring lactone 24 has been reported by Fang and coworkers from Glaxo by applying Sharpless asymmetric dihydroxylation reaction [104]. Other examples of catalytic enantioselective syntheses of CPTs are reviewed by Du in [58], whereas older approaches to racemic CPT are the subject of review by Hutchinson [52]. 

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